Waldenström macroglobulinemia

What every physician needs to know:

Waldenström macroglobulinemia (WM) is a rare low grade B-cell lymphoma. The two most important characteristics of WM are the detection of an immunoglobulin M (IgM) monoclonal gammopathy in the serum and infiltration of the bone marrow with lymphoplasmacytic cells.

WM accounts for approximately 1 to 2% of hematological cancers and there are around 1,500 new cases diagnosed each year in the United States. The median age at diagnosis is 63 to 68 years old, with incidence being higher in Caucasians.

WM is an incurable disease with a median overall survival of 5 to 6 years and a median of disease specific survival of 11.2 years. A recent study in WM by the Southwest Oncology Group reported the 10 year overall survival to be 41%.

Are you sure your patient has Waldenström macroglobulinemia? What should you expect to find?

WM is a heterogeneous disease, where patients can present with a broad spectrum of signs and symptoms. Most patients with the diagnosis of WM have symptoms attributable to tumor infiltration and/or IgM monoclonal protein.

The clinical manifestations of WM related to direct tumor infiltration of the bone marrow are anemia and other cytopenias, which most commonly manifest as: fatigue, shortness of breath, bleeding, or infections.

Hepatosplenomegaly and lymphadenopathy can occur in 20% of patients.

The clinical presentation due to properties of circulating IgM includes hyperviscosity, which results in symptoms such as headache, blurring of vision, and recurrent epistaxis. Other rare presentations include peripheral neuropathy, cryoglobulinemia, coagulopathy, and cold agglutinin disease.

Some patients may also present with B symptoms including night sweats, fever, and weight loss.

Beware of other conditions that can mimic Waldenström macroglobulinemia:

The MYD88 L265P gene mutation is present in over 90% of cases with WM, and CXCR4 mutations are present in about 30-40% of cases. These mutations are important for the diagnosis, prognosis and response to therapy in patients with WM.

WM also needs to be differentiated from IgM Monoclonal Gammopathy of Undetermined Significance (MGUS), if <10% bone marrow infiltration is present at biopsy. IgM MGUS is an early stage of B-cell proliferation, which can evolve into WM with a progression rate of 1.5% per year.

Which individuals are most at risk for developing Waldenström macroglobulinemia?

The main risk factor for developing WM is IgM MGUS, which presents a 50 to 200-fold higher relative risk of developing WM than the general population.

Men have a higher incidence of WM than women with 3.4 per million compared to 1.7 per million.

The incidence of familial WM is relatively high with some reports showing that about 20% of patients with WM have at least one relative with B-cell neoplasm.

Familial WM patients were more likely than unaffected relatives to report history of autoimmune disease, infections and exposure to pesticides, wood dust, and organic solvents.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

WM diagnosis requires evidence of an IgM monoclonal protein and histologic bone marrow infiltration with lymphoplasmacytic cells regardless of the amount of IgM and percent infiltration in the bone marrow. Baseline serum protein electrophoresis, quantitative immunoglobulins, along with bone marrow biopsy and aspiration with immunophenotypic and cytogenetic studies, can therefore make the diagnosis. MYD88 mutations might be helpful to differentiate WM from other conditions.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of Waldenström macroglobulinemia?

Computed tomography (CT) scans of chest, abdomen, and pelvis must be performed for disease staging at initial diagnosis, and for response therapy assessment during the follow up, for patients with extramedullary disease (lymphadenopathy, hepatosplenomegaly). Combined FDG-PET (fluorodeoxyglucose positron emission tomography) CT imaging might be of value in patients with atypical presentation or if there are concerns for transformation into more aggressive lymphoma.

If you decide the patient has Waldenström macroglobulinemia, what therapies should you initiate immediately?

WM is not an emergency itself, but some of the presenting symptoms of WM which require immediate therapy are: symptomatic hyperviscosity, cryoglobulinemia, or moderate to severe cytopenias, resulting from cold agglutinemia or immune related thrombocytopenia.

In the case of hyperviscosity, plasmapheresis should be initiated to achieve rapid paraprotein reduction. After plasmapheresis, patients should be started on therapy for WM as soon as possible. Proteasome inhibitor-based therapy is preferable for immediate disease control in these cases, because of the rapid reduction in IgM. Rituximab can cause an IgM flare in 50% of the patients, and therefore should be avoided as a single agent in patients with high levels of IgM.

More definitive therapies?

The treatment of patients with WM depends on the presence of signs and symptoms of the disease. Asymptomatic patients do not usually need treatment based on the monoclonal protein level alone. The most common reason to initiate therapy in WM is the presence of anemia.

Frontline treatment options for WM include:

Bruton tyrosine kinase inhibitors (ibrutinib)

Proteasome inhibitors (bortezomib, carfilzomib)

Alkylating agents (chlorambucil, cyclophosphamide, bendamustine)

Monoclonal anti-CD20 antibody (rituximab, ofatumumab)

Nucleoside analogs (fludarabine, cladribine)

Combinations of these agents such as fludarabine/rituximab, fludarabine/cyclophosphamide/rituximab, cyclophosphamide/rituximab/dexamethasone, and rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) have been commonly used. These regimens have high response rates, but are also associated with long-term side effects. Alkylating agents and nucleotide analogs are conventional chemotherapeutic agents that inhibit deoxyribonucleic acid (DNA) synthesis. However, recent studies have shown that these agents may induce long-term side effects such as myelodysplasia/leukemia and large cell transformation.

Rituximab has become one of the main therapeutic options of patients with newly diagnosed or relapsed WM, either as a single agent or in combination with chemotherapy or targeted agents. An important consideration in the treatment of patients with rituximab is the potential for rituximab-mediated “IgM flare”, particularly in patients with high IgM levels.

Bortezomib in combination with rituximab with or without dexamethasone (BDR and VR respectively) is commonly used in newly diagnosed WM. The overall response rates with these combinations are higher than 80% but also high rates of neuropathy. The combination of carfilzomib, dexamethasone and rituximab has also shown high and durable response rates without neuropathy.

The combination of bendamustine and rituximab (Benda-R) has been compared in a randomized controlled trial with R-CHOP and has shown higher response rates and longer progression-free survival with a good safety profile. Benda-R might be a good option for patients presenting with lymphadenopathy.

In January 2015, the oral Bruton tyrosine kinase ibrutinib was approved by the FDA for the treatment of patients with symptomatic WM. Ibrutinib has shown to be effective at inducing responses in over 90% of WM patients treated. Mutations in MYD88 and CXCR4 can impact the degree and rapidity of response to ibrutinib.

All the above-mentioned regimens can also be used for the treatment of patients with relapsed/refractory WM.

Maintenance therapy with rituximab is being used in patients with WM after responding to rituximab-containing induction regimens. An observational study showed improvement in progression free and overall survival among patients receiving maintenance rituximab when used at 375mg/m2 every 3 or 6 months over 2 years. Although there is no prospective randomised study addressing the role of maintenance rituximab in WM patients, rituximab maintenance has been prospectively studied in other indolent B-cell lymphomas.

What other therapies are helpful for reducing complications?

Treatment related complications are as follows:

Possible complications of IgM flare include hyperviscosity and cryoglobulinemia, as well as worsening of IgM-related neuropathy. In rare occasions, plasmapheresis is needed to decrease the IgM flare and the co-morbidities associated with it. When rituximab is combined with bortezomib or other agents, the incidence of IgM flare decreases significantly. Another option is to omit rituximab for the first one or two cycles of treatment to prevent IgM flare.

Peripheral neuropathy is one of the adverse effects of bortezomib therapy which usually necessitates dose reductions. Some studies have also shown that peripheral neuropathy is less when bortezomib is given weekly, instead of the twice weekly regimen. Some of the drug therapy used to treat bortezomib induced peripheral neuropathy is: pregabalin, gabapentin, or opioid analgesics.

Another approach is the use of supplements like: vitamin E, alpha lipoic acid, glutathione, or L-carnitine, which might help relief neuropathy in some patients. Emollients like cocoa butter cream can also help alleviate local symptoms.

Herpes zoster prophylaxis is recommended for all patients receiving bortezomib or other proteasome inhibitors.

What should you tell the patient and the family about prognosis?

WM is a treatable but incurable disease.

At least two population-based studies, from Sweden and the US, have shown an improvement in the prognosis of WM patients in the last decade. The median survival from diagnosis is about 10 years with younger patients having longer survival times. In the US study, an improvement in survival was observed regardless of age, sex, extranodal involvement, and US region. Blacks had a worse survival than whites.

In patients who are beginning therapy, factors associated with poor prognosis are age, cytopenias, beta-2-microglobulin levels, serum IgM monoclonal protein level, and organomegaly. Some of these factors are included in the International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSSWM). The 5-year survival for patients with low-risk disease is 87%, while the 5-year survival in patients with high-risk disease is 36%. However, these patients were not treated with rituximab or other novel agents.

Some of the causes of death related to WM include: progressive disease, transformation to aggressive lymphoma, infections, development of myelodysplasia or leukemia, or development of other cancers.

What if scenarios.

One of the complications of WM may be IgM-related neuropathy. In patients with mild neuropathy, the treatment could include plasmapheresis or single agent rituximab therapy. In patients with moderate to severe IgM-related neuropathy, the use of combination therapy or ibrutinib may be preferable to achieve better paraprotein reductions. Use of bortezomib should be avoided in patients with IgM-related neuropathy.

Another complication is autoimmune anemia which should be treated with corticosteroids according to usual protocols.

Infections susceptibility is observed in WM patients and can be managed according to infectious disease protocols, with consideration of intravenous immunoglobulin in patients with severe hypogammaglobulinemia.

Hyperviscosity is another major complication of WM, which is usually managed by urgent plasmapheresis followed by systemic therapy (refer to emergency department for management).

Pathophysiology

The WM original cell is a B-cell arrested before terminal differentiation to plasma cells and after somatic hypermutation in the germinal center. The WM malignant cells express pan B-cell markers: CD19, CD20 and CD22, but usually lack expression of CD5, CD10 and CD23. Several signaling pathways have been involved in WM pathogenesis and are therefore a target for new therapies: BTK, PI3K, BCL2 and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathways are activated. Moreover, epigenetic modifications such as microRNA and histone acetylation seem to be important in WM pathogenesis.

Extrinsic regulation by the bone marrow microenvironment also plays a pivotal role in WM malignant clone survival and proliferation, through cytokines and chemokines upregulation and bone marrow angiogenesis.

Recently, recurrent mutations in the MYD88 and CXCR4 genes have been identified in WM patients. The MYD88 L265P gene mutation can be seen in 90% of WM patients and appears to be an early event in the development of the disease as it can also be seen in a portion of patients with IgM MGUS. The CXCR4 mutation status might serve as a predictor for response to therapy.

What other clinical manifestations may help me to diagnose Waldenström macroglobulinemia?

Some of the following rare clinical symptoms can be a part of the WM heterogenous clinical spectrum:

Amyloidosis is due to deposition of light chains in tissues, and can cause various symptoms such as: peripheral neuropathy, orthostatic hypotension, cardiomyopathy, macroglossia, and periorbital bruising.

Cold agglutinin hemolytic anemia and cryoglobulinemia can also be part of the picture, and are due to the autoantibody activity of IgM.

Other rare manifestations include Schnitzler syndrome (skin rash), and Bing-Neel syndrome with central nervous system manifestations.

If patients are complaining from any peripheral neuropathy symptoms, evaluation for anti-myelin associated glycoprotein, anti-ganglioside M1, anti-sulfatide IgM antibody, cryoglobulinemia, fat pad biopsy with Congo staining for amyloidosis testing, and electromyography must be useful. Other common causes of neuropathy should be ruled out.